Once an individual is infected with herpes simplex virus (HSV), the virus establishes a latent infection in sensory neurons. Periodically, stimuli induce lytic reactivation that results in disease ranging from recurrent oral or genital lesions to severe ocular disease. Initiation of lytic infection as well as reactivation from latency depends upon the coordinated expression of the viral (IE) immediate early genes. These genes are controlled by complex multiprotein enhancer assemblies that consists of viral and cellular components. Studies are designed to identify critical components and investigate their interactions and their biochemical functions in order to provide insights into the mechanisms that mediate viral IE gene expression. The mammalian transcriptional coactivator HCF-1 is one of the essential factors involved in both the assembly of the viral IE enhancer complex and the activation of IE gene transcription. Studies address functions of this coactivator during the viral lytic cycle as well as in normal cellular processes. The importance of both is underscored by the complex viral-cell interactions that impact the lytic and latent states of the viral life cycle. Previous studies have determined that HCF-1 functions as a component of chromatin modification complexes that are essential for modulating the chromatin status of the viral IE genes upon initiation of lytic infection. In addition, signal mediated nuclear transport of HCF-1 in latently infected sensory neurons was correlated with viral reactivation, indicating that HCF-1 and its associated protein components may function as molecular switch to initiate reactivation. In fiscal year 2019, (i) specific depletion of HCF-1 in sensory neurons demonstrated that HCF-1 is required to modulate the epigenetic state of the viral genome to promote the initiation of reactivation; and (ii) the HCF-1 associated Super Elongation Complex promotes reactivation from latency.